In order for T cells to respond to foreign proteins, two signals must be provided by antigen-presenting cells (APCs) to resting T lymphocytes (Jenkins, M. and Schwartz, R. (1987) J. Exp. Med. 165, 302–319; Mueller, D. L., et al. (1990) J. Immunol. 144, 3701–3709). The first signal, which confers specificity to the immune response, is transduced via the T cell receptor (TCR) following recognition of foreign antigenic peptide presented in the context of the major histocompatibility complex (MHC). The second signal, termed costimulation, induces T cells to proliferate and become functional (Lenschow et al. 1996. Annu. Rev. Immunol. 14:233). Costimulation is neither antigen-specific, nor MHC restricted and is thought to be provided by one or more distinct cell surface molecules expressed by APCs (Jenkins, M. K., et al. 1988 J. Immunol. 140, 3324–3330; Linsley, P. S., et al. 1991 J. Exp. Med 173, 721–730; Gimmi, C. D., et al., 1991 Proc. Natl. Acad. Sci. USA. 88, 6575–6579; Young, J. W., et al. 1992 J. Clin. Invest. 90, 229–237; Koulova, L., et al. 1991 J. Exp. Med. 173, 759–762; Reiser, H., et al. 1992 Proc. Natl. Acad. Sci. USA. 89, 271–275; van-Seventer, G. A., et al. (1990) J. Immunol. 144, 4579–4586; LaSalle, J. M., et al., 1991 J. Immunol. 147, 774–80; Dustin, M. I., et al., 1989 J. Exp. Med. 169, 503; Armitage, R. J., et al. 1992 Nature 357, 80–82; Liu, Y., et al. 1992 J. Exp. Med. 175, 437–445). If T cells are only stimulated through the T cell receptor, without receiving an additional costimulatory signal, they become nonresponsive, anergic, or die, resulting in down modulation of the immune response.
The CD80 (B7-1) and CD86 (B7-2) proteins, expressed on APCs, are critical costimulatory molecules (Freeman et al. 1991. J. Exp. Med. 174:625; Freeman et al. 1989 J. Immunol. 143:2714; Azuma et al. 1993 Nature 366:76; Freeman et al. 1993. Science 262:909). B7-2 appears to play a predominant role during primary immune responses, while B7-1, which is upregulated later in the course of an immune response, may be important in prolonging primary T cell responses or costimulating secondary T cell responses (Bluestone. 1995. Immunity. 2:555).
One ligand to which B7-1 and B7-2 bind, CD28, is constitutively expressed on resting T cells and increases in expression after activation. After signaling through the T cell receptor, ligation of CD28 and transduction of a costimulatory signal induces T cells to proliferate and secrete IL-2 (Linsley, P. S., et al. 1991 J. Exp. Med. 173, 721–730; Gimmi, C. D., et al. 1991 Proc. Natl. Acad. Sci. USA. 88, 6575–6579; June, C. H., et al. 1990 Immunol. Today. 11, 211–6; Harding, F. A., et al. 1992 Nature. 356, 607–609). A second ligand, termed CTLA4 (CD152) is homologous to CD28 but is not expressed on resting T cells and appears following T cell activation (Brunet, J. F., et al., 1987 Nature 328, 267–270). In contrast to CD28, CTLA4 appears to be critical in negative regulation of T cell responses (Waterhouse et al. 1995. Science 270:985). Blockade of CTLA4 has been found to remove inhibitory signals, while aggregation of CTLA4 has been found to provide inhibitory signals that downregulate T cell responses (Allison and Krummel. 1995. Science 270:932).
There has been a long-felt need to develop methods of enhancing immune responses. For example, the immune response to certain viruses and to tumor cells has, to date, been difficult to augment using art recognized methods. Methods for enhancing immune responses in general, and in particular to enhance responses to tumor antigens and infectious agents (e.g., viral, bacterial, and/or parasite antigens), would be of great benefit.